Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors

Hui Lin Chua, P. Artur Plett, Carol H. Sampson, Barry Katz, Gilbert W. Carnathan, Thomas J. Macvittie, Keith Lenden, Christie Orschell

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

ABSTRACT: In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.

Original languageEnglish
Pages (from-to)21-38
Number of pages18
JournalHealth Physics
Volume106
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Acute Radiation Syndrome
Granulocyte Colony-Stimulating Factor
Survivors
Bone Marrow
Survival
Radiation
Appointments and Schedules
Medical Licensure
Mass Casualty Incidents
Hematopoietic Stem Cells
Half-Life
pegfilgrastim
Maxy G34
Cell Cycle
Transplantation
Phenotype

Keywords

  • blood
  • bone marrow
  • mice
  • radiation damage

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis
  • Epidemiology

Cite this

Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors. / Chua, Hui Lin; Plett, P. Artur; Sampson, Carol H.; Katz, Barry; Carnathan, Gilbert W.; Macvittie, Thomas J.; Lenden, Keith; Orschell, Christie.

In: Health Physics, Vol. 106, No. 1, 01.2014, p. 21-38.

Research output: Contribution to journalArticle

Chua, Hui Lin ; Plett, P. Artur ; Sampson, Carol H. ; Katz, Barry ; Carnathan, Gilbert W. ; Macvittie, Thomas J. ; Lenden, Keith ; Orschell, Christie. / Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors. In: Health Physics. 2014 ; Vol. 106, No. 1. pp. 21-38.
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